L-type calcium channel antagonists are promising agents for the treatment of cocaine dependence, presumably because they reduce cocaine's rewarding effects associated with abuse liability. We propose two experiments using state-of-the-art human abuse liability assessment techniques to examine the subjective, behavioral, and physiological effects of cocaine both alone and in combination with the L-type calcium channel antagonist, isradipine. Both studies will be double-blind and placebo-controlled using balanced (for sequence and ordinal position) cross-over designs in male and female non treatment seeking cocaine abusers (total n = 42). The first experiment, which is a logical and systematic extension of pre-clinical work and our own preliminary studies, will test the hypothesis that acute isradipine significantly reduces acute cocaine-mediated changes in subjective mood and other abuse liability assessments. As a secondary objective of this experiment, we will characterize the effects of cocaine on cognitive function and physiological response in non-fatigued subjects during drug-taking, and determine if, and by how much, these effects are altered by isradipine. The second experiment will test the hypothesis that repeated isradipine administration will antagonize the rewarding effects of acute cocaine. In addition, as a secondary objective, we will determine if repeated isradipine administration will be well tolerated, produce no adverse effects on cognitive or psychomotor function, and reduce cocaine's pressor effects. In essence, Exp. number I provides a proof-of-concept analysis of isradipine's ability to reduce cocaine's abuse potential. Exp. number 2 directly assesses issues of potential clinical effectiveness and tolerability with which to guide clinical trials. Confirmation that isradipine is well tolerated and effective in the human laboratory would provide a solid rationale to begin clinical trials using this agent for the treatment of cocaine dependent populations. Whereas no pharmacological treatment is yet known or expected to be entirely sufficient in preventing cocaine abuse and dependence, studies such as these should improve our knowledge of mechanistic pharmacological and behavioral processes associated with cocaine use, and may contribute to the development of an effective treatment agent. This project supports NIDA's mission to understand the bio-behavioral effects of cocaine dependence, and to develop effective medications for its treatment.